Regional therapies for treatment of pain

ABSTRACT

Systems and methods for coordinated delivery of a therapeutic agent and low (less than about 20 Hz) and high (greater than about 50 Hz) frequency stimulation therapy are described. The systems include a control unit for coordinating therapy delivery between an infusion device and a pulse generator, such that a therapeutic agent is administered at a predetermined time relative to application of either low frequency or high frequency stimulation. For example, the control unit may instruct the infusion device to deliver therapeutic agent at a predetermined time prior to delivery of low frequency stimulation. Systems that include more than one infusion device or an infusion pump capable of delivering more than one therapeutic agent are also described.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. Nos. 60/700,627, filed on Jul. 19, 2005 and60/761,823, filed on Jan. 25, 2006, which applications are incorporatedherein by reference in their entireties. This application also claimsthe benefit of priority to U.S. Provisional Application Ser. Nos.60/689,168, 60/689,201, 60/689,202, 60/689,203 and 60/689,204, each ofwhich was filed on Jun. 9, 2005.

FIELD

The following disclosure relates generally to medical devices andmethods for treating of pain with implantable medical devices.

BACKGROUND

Pain can be a debilitating disorder that is difficult to treat. Much ofthe difficulty in treating pain may be associated with the varyingphysiological bases for different types of pain and may be due to therather complex neurological basis for each type of pain. While complex,a great deal is known about pain transmission at the cellular andmolecular level.

Referring to FIG. 1, a variety of neuronal cell types may be involved inthe transmission or perception of pain. For example, Aβ, Aδ, and Cprimary afferent 10 fibers transmit signals from the periphery to thespinal cord 20. Cell bodies of the neurons with these fibers lie indorsal root ganglion 30 and their axons pass through dorsal roots 40prior to synapsing in the dorsal horn 50 of the spinal cord 20. Morespecifically, branches of these axons may ascend or descend a fewvertebral segments in the tract of Lissauer, and axon collaterals maysynapse with many neurons in the dorsal horn 50. These afferents 10 maysynapse with inhibitory interneurons 500 or projection neurons 510 thatsend ascending projections through various ascending tracts 60 (see FIG.2), such as the spinothalamic tract, the spinoreticular tract, thespinomesencephalic tract, or the spinocervical tract. The variousascending tracts 60 send projections to the thalamus or other midbrainstructures.

For example, spinothalamic tract projection neurons may terminate in themedial nuclear group of the thalamus, including the central lateralnucleus and the ventral posterior lateral nucleus; spinoreticular tractprojection neurons may terminate in the reticular formation of the ponsor the thalamus; spinomesencephalic tract neurons may project to themesencephalic reticular formation, the lateral part of theperiaqueductal gray region, and other midbrain structures; andspinocervical tract neurons may project to midbrain nuclei and thethalamus, including the ventroposterior lateral and posterior medialnuclei. In these higher centers, in other regions of the brain receivingprojections from these centers, or combinations thereof, pain may beperceived.

Descending fibers originating from, e.g., the periaqueductal graymatter, the nucleus raphe magnus or the nucleus paragigantocellularis,send projections in descending tracts 70 in the dorsolateral funiculus,directly or indirectly, to the dorsal horn 50 of the spinal cord 20,where they may synapse with interneurons or ascending projectionneurons. The descending neurons that synapse with neurons in the dorsalhorn 50 of the spinal cord are typically serotoninergic or noradrenergicneurons and may act to suppress activity of ascending projectionneurons, especially those involved with nociception. Due in part to thelarge number of classes of neurons involved in pain transmission andperception, pain can be difficult to treat. In addition, pain may havedifferent origins in different patients, making pain therapy managementand strategy difficult. For example, some patients may benefit frominhibition of C fiber activity alone. Others may benefit from inhibitionof Aβ fibers. Some may benefit from increased activity of Aα/Aβ fibersand descending neurons.

Further complicating the treatment of pain is the involvement ofsympathetic neurons. Sympathetic neurons include projections in thespinal cord that originate from the brain to interneurons or topreganglionic neurons, interneurons, preganglionic neurons andpostganglionic neurons. Sympathetic projections from the brain includingbrain stem, midbrain and forebrain to preganglionic sympathetic neuronsor interneurons of the spinal cord include projections from brain areassuch as the paraventricular nucleus of the hypothalamus, rostralventrolateral medulla, ventromedial medulla, and caudal raphe nucleus.Preganglionic cell bodies of the sympathetic nerves and associatedinterneurons generally reside within the intermediolateral cell columnof the lateral horn 80 of the spinal cord 20 at C1-S5. Generally,preganglionic sympathetic cell bodies send projections that exit thespinal cord through the ventral roots 90 to synapse with postganglionicneurons in sympathetic ganglia 100. Examples of sympathetic ganglia 100include not only the chain of ganglia on each side of the spinal column,but also the inferior mesenteric, superior mesenteric, celiac,submandibular, otic, and pterygopalatine ganglia. Postganglionic nervessend projections that typically follow the vasculature to innervate endorgans. Activity of sympathetic efferent fibers following peripheralnerve injury may cause burning pain, e.g., causalgia, or reflexsympathetic dystrophy syndrome. This activity is thought to cause painby direct activation of damaged nociceptive afferent neurons or bynonsynaptic sympathetic transmission.

The sympathetic nervous system also comprises afferent fibers 140, whichpass from the peripheral sympathetic system through the ramicommunicantes. Some of these fibers terminate about cell bodies withindorsal root ganglia 30. Cell bodies of some sympathetic afferents may belocated in dorsal root ganglia 30 or sympathetic ganglia 100. Thoseending in sympathetic ganglia 100 may send projections, direct orindirect to the lateral column 80 of the spinal cord 20. Shown in FIG. 1are sympathetic afferent fibers, which project from discs 110 throughsympathetic trunks via sympathetic ganglia 100 enter the spinal cord 20through dorsal roots 40. Nerve endings in the vertebral discs aregenerally located in peripheral third of the disc.

Increased sympathetic activity has been implicated in increased pain insome circumstances and blocking of sympathetic neurons with drugs orelectrical stimulation has been used to treat or prevent acute pain. Inaddition, RF and surgical lesions of the sympathetic chain are used totreat chronic pain. However, these are non-reversible therapies and maybe difficult to repeat.

In addition to synapsing on inhibitory interneurons 500 and/orprojection neurons 510, neurons of Aβ, Aδ, and C primary afferent fibers10 may synapse on sympathetic efferent neurons 600 (see, e.g., FIG. 3).The connections between afferent inputs to the spinal cord andsympathetic efferent outputs may be an important target in the treatmentof pain.

Spinal cord stimulation (SCS), while not perfect, has been useful fortreating pain. The precise mechanism of action of SCS is not fullyunderstood. As shown in FIG. 4, SCS typically involves stimulation viaone or more epidurally placed electrode of a lead 120. FIG. 5 shows analternative perspective view of a portion of a spinal cord 20 withepidural placement of a lead 120. In both FIG. 4 and FIG. 5, the lead120 and its associated electrode(s) are positioned epidurally near thedorsal columns. A depolarizing electrical signal is delivered throughthe electrode(s). In theory, the depolarizing electrical signal excitesascending neurons 700 in the dorsal columns. The ascending neurons 700in the dorsal column send collaterals that synapse with neurons in thedorsal horn 50, including primary afferents, inhibitory interneurons500, and/or projection neurons 510. Stimulation of the dorsal column mayto a lesser extent excite neurons in the descending tract 70, therebyenhancing the pain inhibiting effects of the descending transmissions.In addition, epidural SCS recruits large fibers, such as Aβ fibers,which can excite inhibitory interneurons 500 in the dorsal horn 50,thereby inhibiting transmission of pain signals through projectionneurons 510 that run in ascending tracts 60. While lead 120 placement isin proximity to the dorsal columns, the effects of such electricalstimulation may spread to the dorsal roots 40 through the relativelyconductive cerebrospinal fluid (CSF). Thus as described above, primaryafferent Aβ fibers may be recruited and at least a portion of thetreatment of pain may be due to effects on neurons in the dorsal roots40. However, it is possible that the efficacy of such treatment isattenuated by effects at the dorsal roots 40 through stimulation of,e.g., C-fibers.

The efficacy of epidural electrical stimulation of the dorsal column canbe quite high immediately after lead placement, e.g. approximately 60%for low back pain. However, within a few months the efficacy may drop astolerance develops. For example, efficacy of dorsal SCS for treatmentmay drop to as little as 20% after about six months. The mechanisms forthe development for such tolerance are not well understood. In additionto tolerance, epidural stimulation suffers from increased energy needsfor the stimulation signal to cross the dura 130 and loss or inadvertentstimulation of dorsal roots due to CSF conductance.

Transcutaneous electrical neural stimulation (TENS) is another potentialtherapy for treatment of pain that has been shown to work well in rodentmodels. Many of such animal models involve artificially inducedinflammation in a knee joint of a rat where TENS therapy is applied tothe knee. Such models have shown that high frequency TENS is effectivefor treatment of primary and secondary hyperalgesia as well asmorphine-tolerant secondary hyperalgesia, while low frequency TENS iseffective for secondary hyperalgesia but not morphine-tolerant secondaryalgesia or primary hyperalgesia. In addition, much has been learned fromsuch models about the mechanisms and interactions between peripheralpain and peripherally-applied TENS to central pain neurotransmission.For example, the effect of peripherally-applied TENS on central opioid,serotonin, muscarinic, and noradrenergic neurotransmission has becomebetter understood. However, to date, TENS has not yet been shown to beconsistently effective in treatment of pain, particularly low back pain.For low back pain, TENS may be impracticable as rather large leads andelectrodes would likely be needed to provide a sufficient stimulationsignal to deeper areas such as sympathetic ganglia 100 and dorsal roots40. In addition, a TENS signal capable of stimulating such deeperstructures in humans is also likely to stimulate unintended neuronscausing side effects.

Accordingly, there remains a need for additional therapies to treatpain. Preferably such therapies increase efficacy over existingtherapies or reduce tolerance relative to existing therapies.

SUMMARY

Embodiments of the present invention relate to implantable medicaldevices, systems and methods for coordinating therapy delivery between apulse generator and an infusion device. In various embodiments, systemscomprise a pulse generator and an infusion device that coordinatedelivery of stimulation therapy and therapeutic agent infusion. Thepulse generator and infusion pump may be in communication or may beinstructed to provide therapy in a coordinated fashion. The systems maycomprise a control unit, which may be housed with the pulse generator orinfusion device or may be housed separately from the pulse generator orinfusion pump, to coordinate the therapy.

In an embodiment, the invention provides a system. The system comprisesa pulse generator capable of alternating between generation of a firstelectrical signal and generation of a second electrical signal. Thesystem further comprises first infusion device capable of delivering atherapeutic agent at a rate at a predetermined time based on when thepulse generator switches from generation of the first signal togeneration of the second signal. In addition, the system comprises acontrol unit configured to coordinate the delivery of the therapeuticagent at the rate from the infusion device with the switch from thegeneration of the first signal to the generation of the second signal.

In an embodiment, the invention provides a system that comprises (i) apulse generator capable of alternating between generation of a firstelectrical signal and generation of a second electrical signal, and (ii)an infusion device capable of initiating delivery of a therapeutic agentat a rate during a time when the pulse generator generates the firstsignal and ceasing delivery of the therapeutic agent at the rate duringa time when the pulse generator generates the second signal. The systemfurther comprises a control unit configured to coordinate the initiationof delivery of the therapeutic agent from the infusion device with thegeneration of the first signal and the cessation of delivery of thefirst therapeutic agent from the first infusion device with thegeneration of the second signal.

In an embodiment, the invention provides a system that comprises aninfusion device capable of delivering a therapeutic agent at apredetermined rate and a pulse generator capable of generating a firstelectrical signal and a second electrical signal. The system furthercomprises a control unit configured to coordinate generation of thefirst electrical signal by the pulse generator during a time when theinfusion device is delivering the therapeutic agent at the predeterminedrate and generation of the second electrical signal by the pulsegenerator at a time when the infusion device is delivering thetherapeutic agent at a rate other than the predetermined rate.

In an embodiment, the invention provides a system comprising means fordelivering to a subject a first therapeutic agent, means for deliveringto the subject a first electrical signal having a first frequency, meansfor controlling whether the first or second electrical signal isdelivered to the subject, and means for controlling timing of theadministration of an amount of the first therapeutic agent based onwhether the first or second electrical signal is being delivered.

In an embodiment, the invention provides a system comprising a pulsegenerator capable of alternating between generation of a firstelectrical signal and generation of a second electrical signal and aninfusion device configured to deliver a therapeutic agent at apredetermined time from when the pulse generator switches fromgeneration of the first signal to generation of the second signal.

In an embodiment, the invention provides a method that comprisesidentifying whether a first predetermined electrical signal is beinggenerated by an implantable pulse generator and instructing an infusiondevice to deliver a therapeutic agent at a rate if the predeterminedelectrical signal is being generated.

In an embodiment the invention provides a method that comprisesinstructing an implantable pulse generator to generate a first and asecond electrical signal at predetermined times and instructing aninfusion device to deliver a therapeutic agent at a predetermined timerelative to generation of the first or second electrical signal.

Various embodiments of the invention provide one or more advantages overexisting treatment systems and therapies. The coordinated delivery oftherapeutic agent with particular stimulation parameters may provideincreased efficacy and reduced tolerance. For example, the coordinatedadministration of one or more pain treating agent with high or lowfrequency stimulation should enhance efficacy of either treatment givenalone. In addition, with proper timing of delivery of pain treatingagent and combination with appropriate stimulation, the amount of paintreating agent to be delivered may be reduced so that tolerance may bereduced. These and other advantages will be evident in light of thedescription and figures that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following description, reference is made to the accompanyingdrawings that form a part hereof, and in which are shown by way ofillustration several specific embodiments. It is to be understood thatother embodiments are contemplated and may be made without departingfrom the scope or spirit of the teachings of this disclosure. Thefollowing description, therefore, is not to be taken in a limitingsense.

FIG. 1 is a diagrammatic representation of a cross section of a spinalcord with selected nerve fibers and neurons shown.

FIG. 2 is a schematic view of afferents synapsing with inhibitoryinterneurons or projection neurons in a spinal cord.

FIG. 3 is a diagrammatic representation of a cross section of a spinalcord with selected nerve fibers and neurons shown.

FIG. 4 is a diagrammatic representation of a cross section of a spinalcord with selected nerve fibers and neurons and an epidurally placedlead shown.

FIG. 5 is a diagrammatic representation of a perspective view of aspinal cord with selected nerve fibers and neurons and an epidurallyplaced lead shown.

FIG. 6 is a schematic view of a stimulation system implanted in apatient.

FIG. 7 is a block diagram of an exemplary stimulation system.

FIG. 8 is a flow diagram of a method employing low and high frequencysubcutaneous stimulation.

FIG. 9 is a flow diagram of a method employing low and high frequencysubcutaneous stimulation.

FIG. 10 is a flow diagram of a method employing low and high frequencysubcutaneous stimulation.

FIG. 11 is a diagrammatic representation of a cross section of a spinalcolumn showing subcutaneous placement of a lead.

FIG. 12 is a flow diagram of a method employing subcutaneous stimulationand epidural stimulation.

FIG. 13 is a diagrammatic representation of a cross section of a spinalcolumn showing electrodes placed in proximity to a primary hyperalgesicfield and a secondary hyperalgesic field.

FIG. 14 is a schematic view of an infusion system implanted in apatient.

FIG. 15 is a block diagram of an exemplary infusion system.

FIGS. 16A-B are a block diagrams of an exemplary implantable infusionsystems.

FIGS. 17A-C are flow diagrams of administration of a pain treating agentin conjunction with application of stimulation therapy.

FIGS. 18A-D are flow diagrams of administration of a pain treating agentin conjunction with application of stimulation therapy.

FIG. 19 is a flow diagram of administration of a pain treating agent inconjunction with application of stimulation therapy.

FIGS. 20A-C are block diagrams showing communication between systemscomprising a stimulation module and an infusion module.

FIGS. 21A-B are block diagrams of an exemplary stimulation module andinfusion model, respectively.

FIG. 22 is a block diagram showing communication between systemscomprising a stimulation module, an infusion module and a control unit.

FIGS. 23A-B are block diagrams showing communication between systemscomprising a stimulation module and two infusion modules. FIG. 23B showsthe inclusion of a control unit.

FIGS. 24A-B are flow diagrams of instructing stimulation modules andinfusion modules to deliver therapy in a coordinated manner.

FIGS. 25-30 are flow diagrams of coordinated delivery of stimulationtherapy and pain treating agent therapy.

The drawings are not necessarily to scale.

Reference numbers used in the drawings are not intended to limit aparticular feature of a device, system or method. For example, eventhough reference number 5000 refers to an implantable infusion device inFIG. 14, it will be understood that infusion devices that are notimplantable can be readily substituted in many of the embodimentsdiscussed. In addition, use of different reference numbers to refer tothe same feature, device or method step (e.g., the use of referencenumbers 16, 18 and 120 for leads) does not necessarily indicate that thefeatures, devices, or method steps are not the same or similar. Forexample, reference numbers 16, 18 and 120 refer to leads generally andeach may be the same or different model of lead, depending on thecontext in which it is discussed.

DETAILED DESCRIPTION

In the following description, reference is made to the accompanyingdrawings that form a part hereof, and in which are shown by way ofillustration several embodiments of the invention. It is to beunderstood that other embodiments are contemplated and may be madewithout departing from the scope or spirit of the present invention. Thefollowing detailed description, therefore, is not to be taken in alimiting sense. Instead, the scope of the invention is to be defined inaccordance with the appended claims.

The disclosure provided herein relates generally to apparatuses,systems, and methods for treating pain. The apparatuses, systems, andmethods include application of electrical stimulation via one or moreimplantable electrode. At least one electrode is implantedsubcutaneously in proximity to a source of pain of a patient. Theelectrical stimulation may be applied to a broad region of tissue. Thestimulation may contain high frequency or low frequency components andmay vary between high and low frequency stimulation. The apparatuses,systems, and methods also include administering a pain treating agent tothe subject. The timing and rate of administration of the pain treatingagent may be tailored and controlled relative to the timing of theapplication of electrical stimulation to enhance therapy. The paintreating agent may be administered via an implantable pump.

Generally speaking, the teachings presented herein are applicable totreatment of any type of pain. For exemplary purposes, back pain will bediscussed in greater detail herein than pain originating from otherregions of the body.

Application of an electrical signal to subcutaneous regions fortreatment of pain in humans may allow for some of the benefitsassociated with TENS therapy as applied to animal models of pain.However, as opposed to TENS therapy, subcutaneous stimulation may allowfor finer control of the cells to be stimulated, thereby reducingpotential undesired effects relative to TENS. In addition, applicationof high and low frequency stimulation results in more effective therapyfor a wider variety of types of pain, and alternating between high andlow frequency stimulation may result in reduced tolerance relative totypical SCS. Further, control of what subcutaneous structures, includingthe spinal column, receive high or low frequency stimulation may beachieved by subcutaneous placement of electrodes. Subcutaneous placementof electrodes may also allow for a broader area of stimulation than SCSand may result in increased efficacy for treating pain.

The additional application of a pain treating agent may further enhanceefficacy of the pain treatment. The efficacy may further be enhanced bycontrolling the timing of the administration of the pain treating agentrelative to the timing of the electrical stimulation. Devices andsystems capable of delivering therapeutic agents at predetermined timesrelative to application of either high or low frequency stimulation alsooffer advantages relative to currently available systems and methods.

DEFINITIONS

All scientific and technical terms used in this application havemeanings commonly used in the art unless otherwise specified. As used inthis application, the following words or phrases have the meaningsspecified.

As used herein “electrical stimulation” or “stimulation” meansapplication of an electrical signal that may be either excitatory orinhibitory to a muscle or neuron that is directly affected by thesignal. It will be understood that an electrical signal may be appliedto one or more electrodes with one or more return electrodes.

As used herein “or” means and/or unless specifically or implicitly (suchas with a preceding “either”) stated otherwise.

As used herein “high frequency” means greater than about 50 Hz.Accordingly, high frequency includes greater than about 150 Hz, betweenabout 50 Hz and about 75 Hz, etc.

As used herein “low frequency” means less than about 20 Hz. Accordinglylow frequency includes between about 10 Hz and about 20 Hz, less thanabout 10 Hz, etc.

As used herein an electrode placed “in proximity to a source of pain”means an electrode placed at a location capable of producing a directelectrical effect on tissue that is the source of pain or tissue that ifstimulated would result in reduction in pain. Preferably, the placementis such that a stimulation signal delivered by the electrode affectsintended tissue and minimizes effects on unintended tissue. For example,an electrode may be placed in proximity to nerves, muscles, or ligament.

As used herein “in proximity to a structure of the back” means anelectrode placed at a location capable of producing a direct electricaleffect on the structure of the back to which the electrode is placed inproximity. By way of example, the electrode may be placed about 5 mm orless from a structure of the back. The structures of the back that maybe a source of pain or that may result in pain reduction if stimulated,include discs, facet joints, nerve roots or ganglions, sympatheticchain, and the like, as well as ligaments and muscles. As used herein,the spinal cord will not be considered “a structure of the back”, butrather will be referred to separately.

As used herein “epidural” means situated upon the dura or in very closeproximity to the dura.

As used herein “pain treating agent”, “therapeutic agent”, and the likemean a therapeutic molecule or composition of ameliorating foralleviating one or more symptoms of intended disease, disorder orcondition or improving one or more underlying physiological basis of thedisease, disorder or condition. A pain treating agent may treat one ormore of nociceptive pain, inflammatory pain, and neuropathic pain. Itwill be understood that “different” therapeutic agents, as used herein,can refer to the same therapeutic molecule present in a composition atdifferent concentrations.

As used herein “treating pain”, “pain treatment”, and the like meanalleviating or ameliorating one or more symptoms associated with pain orimproving one or more etiological factors associated with pain.

The term “comprises” and variations thereof do not have limiting meaningwhere these terms appear in the accompanying description and claims.Moreover, unless otherwise specified, “a,” “an,” “the,” and “at leastone” are used interchangeably and mean one or more than one. Thus, forexample, an infusion device that comprises “a” reservoir can beinterpreted to mean that the device includes “one or more” reservoirs.

Stimulation

Any present or future developed stimulation system capable of providingan electrical signal to one or more regions in proximity to a source ofpain of a patient to treat pain may be used in accordance with theteachings provided herein. Referring to FIG. 6, a schematic view of apatient 15 having an implant of an exemplary stimulation system usefulfor applying an electrical signal in proximity a structure of the backof the patient 15 is shown. The exemplary system employs an implantablepulse generator (IPG) 14 to produce a number of independent stimulationpulses which are sent to a region in proximity to a structure of theback by insulated leads 16 and 18 coupled to the spinal cord by one ormore electrodes 16A, 18A (FIG. 7). The one or more electrodes 16A, 18Amay be attached to separate conductors included within a single lead.Any known or future developed lead 16, 18 or electrode 16A, 18A usefulfor applying an electrical stimulation signal in proximity to apatient's 15 spinal cord 12 may be used. For example, the leads 16, 18may be conventional percutaneous leads, such as PISCES® model 3487A soldby Medtronic, Inc. In certain circumstances it may be desirable toemploy a paddle-type lead. Any known or future developed implantablepulse generator may be used in accordance with the teachings of thepresent disclosure. For example, IPG 14 may be an ITREL® II or Synergypulse generator available from Medtronic, Inc, Advanced NeuromodulationSystems, Inc.'s Genesis® pulse generator, or Advanced BionicsCorporation's Precision® pulse generator. One of skill in the art willrecognize that the above-mentioned pulse generators may beadvantageously modified to deliver therapy in accordance with theteachings of this disclosure.

The exemplary system in FIG. 6 employs a programmer 4000 which iscoupled via a conductor 22 to a radio frequency antenna 24. This systempermits attending medical personnel to select the various pulse outputoptions after implant using radio frequency communications. While theexemplary system employs fully implanted elements, systems employingpartially implanted elements may also be used in accordance with theteachings provided herein.

Referring to FIG. 7, a block diagram of an exemplary stimulation systemis shown. IPG 14 contains a signal generation module 1000 and a controlmodule 1010. The control module 1010 is operably coupled to the signalgeneration module 1000 and instructs signal generation module 1000regarding the signal to be generated. For example, at any given time orperiod of time, control module 1010 may instruct signal generationmodule 1000 to generate an electrical signal having a specified pulsewidth, frequency, intensity (current or voltage), etc. Control module1010 may be preprogrammed prior to implantation or receive instructionsfrom programmer 4000 (or another source) through any known or futuredeveloped mechanism, such as telemetry. Control module 1010 may includeor be operably coupled to memory to store instructions for controllingsignal generation module and may contain a processor for controllingwhich instructions to send to signal generation module 1000 and thetiming of the instructions to be sent to signal generation module 1000.Leads 16, 18 are operably coupled to signal generation module 1000 suchthat a stimulation pulse generated by signal generation module 1000 maybe delivered via electrodes 16A, 18A.

While two leads 16, 18 are shown in FIGS. 6-7, it will be understoodthat any number of one or more leads may be employed. In addition, whileFIG. 7 shows two electrodes 16A, 16B, 18A, 18B per lead 16, 18, it willbe understood that any number of one or more electrodes per lead may beemployed. Stimulation pulses are applied to electrodes 16A and 18A(which typically are cathodes) with respect to a return electrode 16B,18B (which typically is an anode) to induce a desired area of excitationof electrically excitable tissue in proximity to a source of pain. (Acathode has a more negative potential with respect to an anode, and theelectrical current caused by the cathode tends to induce an actionpotential whereas the electrical current caused by the anode tends toinhibit an action potential.) A return electrode 16B, 18B, such as aground or other reference electrode, as shown in FIG. 7 is located onsame lead 16, 18 as stimulation electrode 16A, 18A. However, it will beunderstood that a return electrode may be located at nearly anylocation, whether in proximity to the stimulation electrode 16A, 18A orat a more remote part of the body 15, such as at a metallic case of apulse generator 14. It will be further understood that any number of oneor more return electrodes may be employed. For example, there can be arespective return electrode for each cathode such that a distinctcathode/anode pair is formed for each cathode.

Stimulation Parameters

Various stimulation parameters may be applied to a stimulation signaldelivered at one or more electrodes to stimulate or inhibit neurons atone or more locations. Any stimulation parameter may be varied,including frequency and amplitude (current or voltage), pulse width,etc. Various stimulation parameters may be applied at one or morelocation until therapy is optimized.

Stimulation signals of high and low frequencies can have differenttherapeutic effects; e.g., high frequency stimulation can reduce primaryhyperalgesia (hyperalgesia in the area of injury) and low frequency canreduce secondary hyperalgesia (hyperalgesia outside the area of injury).Also, alternating between high and low frequency stimulation can inhibitdevelopment of tolerance to either frequency since differentphysiological mechanisms are involved.

In addition, low frequency stimulation is likely to stimulate motorneurons, and may cause pulsations in some muscles. This is a benign sideeffect and is known for both spinal cord stimulation and TENS. Incertain circumstances motor stimulation may be desirable. In essence, itmay be like applying a massage, which is the basis for much acupuncturethat uses electrical stimulation via needles. Accordingly, an example ofthe use of both low and high frequencies is to apply the low frequencysignal/burst to massage muscles and the high frequency signal/burst tosuppress pain. The high frequency signal/burst might not be followed bymuscle contraction, but it might send pain suppression via muscle orother afferent fibers.

Also, stimulation at low versus high frequency may produce differentmechanisms of pain relief and may be useful for treating different typesof pain. For example, low frequency TENS has been shown to involve bothbrain stem and spinal opioid mechanisms and may be useful for treatingnociceptive pain. High frequency TENS may be more beneficial fortreatment of neuropathic pain. Therapy employing both low and highfrequency may be useful for treating mixed pain.

Referring to FIG. 8, a low frequency stimulation signal may be appliedto subcutaneous tissue in proximity to a source of pain 2000 and a highfrequency stimulation signal may be applied to subcutaneous tissue inproximity to a source of pain 2010. Stimulation signals at the same oneor more electrodes may comprise high frequency and low frequencysignals. The high and low frequency signals may be applied at the same(e.g., interlaced) or different times. In an embodiment, high frequencysignals are applied at a different set of one or more electrodes thanlow frequency signals. It will be understood that the different sets ofelectrodes may contain electrodes in common. Regardless of whether thestimulation electrodes are the same or different, there may be common orseparate one or more ground electrodes for the high and low frequencysignals.

High frequency signals may be applied at the same time as low frequencysignals. High frequency signals may be applied at a different time thanlow frequency signals. Application of high frequency signals and lowfrequency signals may be alternated. For example, high frequency signalsapplied for, e.g., between about one second and about eight hours may bealternated with low frequency signals applied for, e.g., between aboutone second and about eight hours. The signals may be alternated in apatterned manner or a random manner. The signals may be alternated inresponse to a sensed signal.

As described herein, delivering high and low frequency signals in shortperiods could increase therapy effectiveness. Because high and lowfrequency have different mechanisms, each frequency could be deliveredfor a short period of time, turned off while the other frequency isdelivered, and then restarted before the pain relief has decreased. Thetwo frequencies could also be delivered simultaneously, or interleaved.In another example, if the goal is to stimulate muscle to produce amassage-like effect, the delivery period may be several minutes, e.g.about 1 to about 10 minutes. It may take about 1 minute for the massageto be perceived; after about 10 minutes it may become irritating. Inanother example, if the intent is to minimize tolerance, the period(specifically the off time) may be on the order of several hours toallow the neurons to return to baseline status after stimulation isturned off.

Duty cycle is the ratio of time spent in delivery of each burst. Thiscan be fixed, e.g., at 3 seconds of high frequency stimulation: 2seconds low frequency stimulation. Or, alternatively, the duty cycle mayvary over time, in a regular manner or irregular, nearly random manner.The length of the bursts may be seconds to minutes long, or may be asshort as a small fraction of second, unperceptable to the patient. Thepulses in each burst may have different amplitudes or pulse widths. Thepulses may be constant current or constant voltage.

Exemplary pulses that may be delivered include alternating bursts of 200pulses at 80 Hz with 50 pulses at 15 Hz. When using the same cathodesand anodes, an exemplary pulse might include a higher frequency seriesof pulses, e.g, at 130 Hz and a different amplitude or pulse width orboth at 5 Hz.

Electrode Placement

One or more electrodes may be placed subcutaneously in proximity to apatient's source of pain to deliver a stimulation pulse in accordancewith the teachings of the present disclosure. Referring to FIG. 9, atleast one set of one or more electrodes is implanted subcutaneously inproximity to a source of pain 2100. A low frequency signal is thenapplied to the subcutaneous region via at least one of the one or moreelectrodes 2110 and a high frequency signal is applied to thesubcutaneous region via at least one of the one or more electrodes 2120.Alternatively, as shown in FIG. 10, a second set of one or moreelectrodes (e.g., on a second lead) may be implanted subcutaneously 2130and the low frequency signal 2140 and high frequency signal 2150 may beapplied via at least one of the first or second set of one or moreelectrodes.

Referring to FIG. 11, one example of subcutaneous placement of a lead320 in proximity to a structure of the back is shown. In FIG. 11, adiagrammatic representation of cross section of vertebrae 150 is shown.The lead 320 may comprise one or more electrodes 430, which may beplaced in proximity to, e.g., one or more sympathetic afferent 140neurons or fibers, one or more sympathetic ganglions 100, or one or moredorsal root ganglions 30. Of course more than one lead 320 may be usedto place the one or more electrodes 430 in proximity to the one or morestructures. It will be understood that one or more electrodes may alsobe placed in proximity to discs, facet joints, muscles, ligaments orother structures in proximity to the spinal cord, such that anelectrical stimulation signal may be applied to such structures via theelectrode(s). In addition, multiple leads 320 may be used to positionone or more electrodes 430 over one or more additional vertebral levels.Two, three, four, five, six, seven, or more vertebral levels may becovered in such a manner. Alternatively, a lead 320 may be placedsubstantially parallel to the spinal cord to allow for electrodeplacement over more than one vertebral level. In general, subcutaneousplacement may serve to provide more specific delivery of a stimulationsignal, and thus less potential side effects than TENS and may prove tobe more efficient than epidural electrical stimulation for relief ofchronic pain. While FIG. 11 shows unilateral placement of lead 320 andelectrodes 430, it will be understood that bilateral placement of leads320 and electrodes 430 is also contemplated and may be desirable.

While FIG. 11 shows an example of subcutaneous lead placement inproximity to structures of the back, it will be understood that theteachings disclosed herein may be applied to other subcutaneous regionsof a patient. For example, the lead may be placed subcutaneously inproximity to a patient's knee, elbow, shoulder, leg, etc. to treat painarising from such peripheral regions. The lead for subcutaneousstimulation may be placed and anchored near a peripheral nerve organglion. It may also be placed deliberately farther away, e.g., acentimeter or more, from a given nerve or ganglion, to minimize sideeffects or recruitment of small fibers that may be nociceptors. It maybe placed near muscles, or near nerves innervating muscles, toespecially affect muscle afferent or efferent nerves.

In various embodiments, one or more stimulation signal is applied tomore than one structure. In an embodiment, at least one of the more thanone structures is selected from the group consisting of a sympatheticafferent 140 neuron or fiber and a sympathetic ganglion 100.

In various embodiments, in addition to the one or more subcutaneouslyplaced electrode, one or more electrode is placed epidurally to delivera stimulation pulse to the patient's spinal cord. Referring to FIG. 12,a first set of one or more electrodes is implanted subcutaneously 2100,e.g. in proximity to a source of pain, and a second set of one or moreelectrodes is implanted epidurally 2200. Of course it will be understoodthat one set of electrodes (e.g, on one lead) may have electrodesimplanted subcutaneously and epidurally. Low frequency stimulation isapplied to at least one of the first set of one or more electrodes 2210,and high frequency stimulation is applied to at least one of the secondset of electrodes 2220. Accordingly, one or more epidurally-placedelectrodes may be used to deliver high frequency stimulation, while oneor more subcutaneously placed-electrodes may be used to deliver lowfrequency stimulation (or high frequency stimulation). Of course, one ormore epidurally placed electrodes may be used to deliver low frequencystimulation, while one or more subcutaneously placed electrodes may beused to deliver high frequency stimulation (or low frequencystimulation).

In an embodiment representatively shown in FIG. 13, one or moreelectrodes 3020, whether epidurally placed or subcutaneously placed, areplaced at a spinal level or in a body region having afferent fiberscorresponding to a spinal level at which primary hyperalgesia is sensed3000 (“primary hyperalgesic field”). One or more electrodes 3030 areplaced at a spinal level or in a body region having afferent fiberscorresponding to a spinal level at which secondary hyperalgesia issensed 3010 (“secondary hyperalgesic field”). Of course the primaryhyperalgesic field may extend over more than one vertebral level 3040,and it may be desirable to place more than one electrode such that asubstantial area in both the primary and secondary hyperalgesic fieldmay directly receive the electrical stimulation signals. In anembodiment, high frequency stimulation is applied via the electrodesplaced in proximity to the primary hyperalgesic field and low frequencystimulation is applied via the electrodes placed in proximity to thesecondary hyperalgesic field. In certain circumstances, it may bedesirable to apply both low and high frequency stimulation to thesecondary hyperalgesic field.

Delivery of Pain Treating Agents

Pain treating agents may be administered in any medically acceptablymanner, such as orally, parentally, epidurally, or intrathecally. Invarious embodiments, one or more pain treating agent is administered viaan infusion system. Any present or future developed infusion systemcapable of delivering a pain treating agent to a patient may be used inaccordance with the teachings provided herein. The infusion system mayinclude implantable components. One example of a suitable implantableinfusion system that may be used in accordance with the teachingspresented herein is Medtronic's SynchroMed II infusion device.

Referring to FIG. 14, a schematic view of a patient 15 having an implantof an exemplary infusion system useful for delivering a pain treatingagent is shown. The exemplary system employs an implantable infusiondevice 5000. The implantable infusion device 5000 comprises a pump 5010operable coupled to a reservoir 5020 (see FIG. 15) that may house one ormore pain treating agent. The exemplary system includes a catheter 5030operably coupled to the pump 5010. Catheter 5030, as show in FIG. 14,has a proximal end 5032 and a distal end 5034 adapted to be implanted ina subject. Between (and including) the proximal end 5032 and the distalend 5034, catheter 5030 comprises one or more delivery regions (notshown) through which the pain treating agent may be delivered. Theimplantable infusion device 5000 may have a port (not shown) into whicha hypodermic needle can be inserted to inject a quantity of paintreating agent into reservoir 5020. Infusion device 5000 may have acatheter port (not shown) to which proximal end 5032 of catheter 5030may be coupled. Infusion device 5000 may be operated to discharge apredetermined dosage of pain treating agent into a target region of apatient 15. As shown in FIG. 15, infusion device 5000 may comprise acontrol unit 5040 to control the amount of pain treating agent deliveredby the infusion device 5000. Control unit 5040 may contain amicroprocessor or similar device that can be programmed or deliverinstructions to control the amount of therapeutic agent delivered. Asshown in FIG. 15, control unit 5040 may be operably coupled to pump 5010to control output of pain treating agent. Alternatively, control unit5040 may be operably coupled to one or more valves (not shown) betweenreservoir 5020 and a delivery portion of catheter 5030 to control flowof pain treating agent, which alternative may be beneficial for infusiondevices 5000 lacking a readily controllable pumping mechanism. Controlunit 5040 may be in wireless communication (e.g., through telemetry)with an external programmer 5050 or similar control unit. With the useof a programmable device 5000, a controlled amount of pain treatingagent may be delivered over a specified time period and different dosageregimens may be programmed for different patients 15. Those skilled inthe art will recognize that a programmed infusion device 5000 allows forstarting conservatively with lower doses and adjusting to a moreaggressive dosing scheme, if warranted, based on safety and efficacyfactors.

If it is desirable to administer more than one pain treating agent, morethan one agent can be mixed into a composition present in the reservoir5020. The local administration of more than one therapeutic agent canalso be accomplished by using more than one infusion device 5000, withthe respective reservoirs 5020 of each infusion device 5000 housing adifferent therapeutic agent. Alternatively and as shown in FIGS. 16A-B,infusion device 5000 may have more than one reservoir 5020, which eachreservoir 5020A, 5020B housing additional compositions comprisingadditional pain treating agents. While only two reservoirs are shown inFIGS. 16A-B, it will be understood that more than two reservoirs may bepresent.

FIG. 16A shows one example of an infusion device 5000 having more thanone reservoir 5020. In FIG. 16A, valve 5050 is disposed betweenreservoirs 5020A, 5020B and pump 5010 and is operably coupled toreservoirs 5020A, 5020B and pump 5010. Valve 5050 may be operablycoupled to and controlled by control unit 5040 (not shown in FIGS.16A-B) such that pump 5010 may draw from the appropriate reservoir5020A, 5020B to deliver appropriate therapeutic agent. One or morecatheters 5030 may be fluidly coupled to pump 5010 to delivertherapeutic agent to desired locations of the patient 15.

FIG. 16B shows another example of an infusion device 5000 having morethan one reservoir 5020A, 5020B. In FIG. 16B each reservoir 5020A, 5020Bis coupled to a pump 5010A, 5010B such that each pump 5010A, 5010B maydraw fluid from a reservoir 5020A, 5020B housing a different paintreating agent. One or more catheters 5030 may be fluidly coupled topump 5010A, 5010B to deliver therapeutic agent to desired locations ofthe patient 15. If only one catheter (not shown) is operably coupled topumps 5010A, 5010B, a valve (not shown) or similar device may beemployed between pump 5010A, 5010B and catheter (not shown in FIG. 16B).

According to various embodiments of the invention, a pain treating agentis administered intrathecally to a patient 15. FIG. 14 illustrates asystem adapted for intrathecal delivery of a pain treating agent. Asshown in FIG. 14, an infusion system or device 5000 may be implantedbelow the skin of a patient 15. Preferably the infusion device 5000 isimplanted in a location where the implantation interferes as little aspracticable with patient activity. One suitable location for implantingthe infusion device 5000 is subcutaneously in the lower abdomen. Forintrathecal delivery, catheter 5030 may be positioned so that the distalend (not shown in FIG. 14) is located in the subarachnoid space of thespinal cord such that a delivery region (not shown) of catheter is alsolocated within the subarachnoid space. It will be understood that thedelivery region can be placed in a multitude of locations to directdelivery of a therapeutic agent to a multitude of locations within thecerebrospinal fluid of the patient 15. The location of the distal end(not shown) and delivery region(s) of the catheter 5030 may be adjustedto improve therapeutic efficacy. While not shown, it will be understoodthat infusion devices or systems 5000 may be used to deliver therapeuticagent to subcutaneous or other locations in proximity to spinalstructures, in proximity to a source of pain, or practically any otherlocation of the body to which a delivery region of a catheter 5030 maybe placed.

Pain Treating Agents

Pain treating agents may be administered in addition to application ofstimulation therapy as described hereinabove. Pain treating agents maybe administered at any time relative stimulation therapy. For example,pain treating agents may be administered throughout stimulation therapy,may overlap with one or more portions of stimulation therapy, mayalternate with stimulation therapy, or may be coordinated to bedelivered at a predetermined time relative to stimulation therapy.

Any medically acceptable pain treating agent may be administeredaccording to the teachings provided herein. Non-limiting examples ofpain treating agents include analgesics, anesthetics, andanti-inflammatory agents. Pain treating agents may be administeredlocally or systemically and may be administered to one or more locationsor by one or more routes. For example, a pain treating agent may beadministered intrathecally or subcutaneously, e.g. in proximity to thespinal cord or in proximity to a site of pain.

Pain treating agents for which it may be beneficial to administer inproximity to a site of pain include anti-inflammatory agents such assteroids, NSAIDS, TNF-alpha inhibitors (soluble receptors, antibodies,etc.), local anesthetics, and NMDA antagonists (ketamine, etc.). Forback pain, such as chronic low back pain, a pain treating agent may bedelivered to cover spinal discs, the sympathetic chain, nerve roots,sympathetic ganglia, etc. The pain treating agent may be delivered suchthat it provides bilateral and multi-segmental coverage.

Some exemplary pain treating agents that may be suitable for supraspinal(e.g., intracerebroventricular or intraparenchymal), intrathecal orepidural delivery include opioid agonists, alpha2 adrenergic agonists(clonidine (α_(2a)), moxonidine (α_(2c)), etc.), serotonin agonists andreuptake inhibitors, adenosine agonists, and the like. Agents, such asopioid agonists, may be delivered to both the brain and the spine toproduce synergistic effects. To achieve supraspinal administration, paintreating agents may be delivered into the intrathecal space and movethrough cerebrospinal fluid into the brain (as described in, e.g., U.S.patent application Ser. No. 10/745,731, entitled “Method of deliveringdrug to the brain via the spinal canal,” filed Dec. 23, 2003).

For pain treating agents that are to be administered intrathecally orotherwise injected or infused, the agents may be formulated intoinjectable compositions. Injectable compositions include solutions,suspensions, and the like. Injectable solutions or suspensions may beformulated according to techniques well-known in the art (see, forexample, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., MackPublishing Co., Easton, Pa.), using suitable dispersing or wetting andsuspending agents, such as sterile oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

Solutions or suspensions comprising a pain treating agent may beprepared in water, saline, isotonic saline, phosphate-buffered saline,and the like and may optionally be mixed with a nontoxic surfactant.Dispersions may also be prepared in glycerol, liquid polyethylene,glycols, DNA, vegetable oils, triacetin, and the like and mixturesthereof. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms. Pharmaceutical dosage forms suitable for injection orinfusion include sterile, aqueous solutions or dispersions or sterilepowders comprising an active ingredient in which powders are adapted forthe extemporaneous preparation of sterile injectable or infusiblesolutions or dispersions. Preferably, the ultimate dosage form is asterile fluid and stable under the conditions of manufacture andstorage. A liquid carrier or vehicle of the solution, suspension ordispersion may be a solvent or liquid dispersion medium comprising, forexample, water, ethanol, a polyol such as glycerol, propylene glycol, orliquid polyethylene glycols and the like, vegetable oils, nontoxicglyceryl esters, and suitable mixtures thereof. Proper fluidity ofsolutions, suspensions or dispersions may be maintained, for example, bythe formation of liposomes, by the maintenance of the required particlesize, in the case of dispersion, or by the use of nontoxic surfactants.The prevention of the action of microorganisms can be accomplished byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In manycases, it will be desirable to include isotonic agents, for example,sugars, buffers, or sodium chloride. Prolonged absorption of theinjectable compositions can be brought about by the inclusion in thecomposition of agents delaying absorption—for example, aluminummonosterate hydrogels and gelatin. Excipients that increase solubility,such as cyclodextrin, may be added.

Sterile injectable compositions may be prepared by incorporating a paintreating agent in the required amount in the appropriate solvent withvarious other ingredients as enumerated above and, as required, followedby sterilization. Any means for sterilization may be used. For example,the injectable composition may be autoclaved or filter sterilized. Inthe case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum drying andfreeze-drying techniques, which yield a powder of the active ingredientplus any additional desired ingredient present in a previouslysterile-filtered solutions. Injectable compositions may be heat treatedor sterilized by autoclaving.

Pain treating agents may be present in compositions at any acceptableconcentration. Non-limiting examples of concentrations of pain treatingagents are shown in the following table for exemplary purposes:

TABLE 1 Exemplary suitable concentration ranges for exemplary paintreating agents Pain Treating Agent Concentration (mg/ml) Morphine 10-50Hydromorphone  1-50 Bupivacaine 2.5-25  Clonidine 0.05-10   Ketamine 0.5-100

Pain treating agents may be administered at any acceptable dosage.Non-limiting examples of daily dosages of pain treating agentsadministered intrathecally are shown in the following table forexemplary purposes:

TABLE 2 Exemplary suitable dosage ranges for exemplary pain treatingagents Pain Treating Agent Daily Dose Morphine 1-5 mg* Hydromorphone1-15 mg Fentanyl 10-150 μg Methadone 5-60 mg Merperidine 30-60 mgBupivacaine 2.5-25 mg Ropivacaine 10-150 mg Clonidine 10-1200 μgKetamine 40-50 mg *For purposes of example, 1-5 mg/day of morphineintrathecal corresponds roughly to 75-375 mg/day oral

It will be understood that the use of combination therapy may providefor increased efficacy while allowing for use of lower doses of eachagent in the combination therapy (relative to if any agent were usedalone in monotherapy). Decreased doses of each individual agent incombination therapy may limit side effects associated with any one ofthe individual agents. For example, combination therapy with clonidineand morphine may allow for a decreased dose of morphine. By decreasingmorphine exposure, tolerance and dose escalation of the morphine can bereduced. In certain circumstances, it may be desirable to initiatetherapy with a combination therapy rather than with monotherapy. Forexample, initiating combination therapy, instead of adding a second paintreating agent to an ongoing therapy in which significant tolerance hasalready developed, may be desirable.

Coordinated Stimulation and Infusion for Treating Pain

Pain treating agents, whether alone or in combination, may beadministered in combination with stimulation. In various embodiments,pain treating agents may be administered during periods of high or lowfrequency stimulation. Preferably, a drug having a synergistic effectwith either high or low frequency stimulation is administered at theappropriate time. For example, a μ-opioid agonist, such as morphine, isadministered during a period of low frequency stimulation or a δ-opioidagonist, such as dynorphin or SNC-80, or an α2 adrenergic agonist, suchas clonidine, is administered during a period of high frequencystimulation. Of course it will be understood that the timing of theadministration of the pain treating agent may be adjusted such that thepain treating agent is present at a desired body location at a time wheneither the low or high frequency stimulation is delivered. Accordingly,the pain treating agent may be administered at a predetermined timerelative to the low or high frequency stimulation to allow for the drugto diffuse to a body location where an enhanced paint treating effectmay be experienced by the patient in combination with the stimulation.The time for a pain treating agent to reach a desired location will beknown to one skilled in the administration of such agents. By way ofexample, intrathecal administration of morphine may take from about 30minutes to about 120 minutes to reach intended spinal receptors insufficient concentration to produce a clinical effect. If it isdesirable to have an agent act in the brain via intrathecaladministration, it may be take about one additional hour for the agentto reach the brain. For example, if it is desired to have morphinepresent in the patient's brain at a time when low frequency stimulationis applied, it may be desirable to administer morphine intrathecallyabout 90 minutes to about 180 minutes prior to delivering the lowfrequency stimulation.

Examples of how pain treating agents may be administered in conjunctionwith stimulation therapy are shown in FIGS. 17-19. As shown in FIG. 17A,pain treating agent may be administered (5120) following application oflow frequency stimulation (5100) and high frequency stimulation (5110).FIG. 17B shows a pain treating agent may be administered (5120) betweenapplication of low frequency stimulation (5100) and high frequencystimulation (5130), and FIG. 17C shows a pain treating agent may beadministered (5120) prior to application of low frequency stimulation(5100) and high frequency stimulation (5130). Regardless of when, inrelation to application of stimulation, a pain treating agent isadministered, the application of a pain treating agent may beadministered in a cyclic fashion relative to application of stimulationas shown in FIGS. 17A-C. Such cyclic administration of pain treatingagents and high and low frequency stimulation may reduce tolerance toany one or more of the therapies (i.e., administration of a paintreating agent 5120, application of low frequency stimulation 5100, andapplication of high frequency stimulation 5110). Of course, the paintreating agent may be administered at the same time as either high orlow frequency stimulation to produce enhanced pain relief.

As shown in FIGS. 18A-D, a pain treating agent whose effect may bepotentiated by concurrent administration of either low or high frequencystimulation may be administered in conjunction with either low or highfrequency stimulation. As shown in FIGS. 18A-B, a μ-opioid agonist maybe administered in conjunction with low frequency stimulation. It willbe understood that agents other than μ-opioid agonists that could bebeneficially combined with low frequency stimulation may also beadministered in conjunction with low frequency stimulation. A μ-opioidagonist may be administered (5130) prior to beginning application of lowfrequency stimulation to a subcutaneous region in proximity to a sourceof pain (5140), as shown in FIG. 18A. This may allow the μ-opioidagonist time to diffuse to its location of action so that when the lowfrequency stimulation is applied, the pain treating effects may becumulative (or preferably more than cumulative). Alternatively, as shownin FIG. 18B a μ-opioid agonist may be administered (5130) following theonset of application of low frequency stimulation to a subcutaneousregion in proximity to a source of pain (5140). This may allowsufficient time for cellular responses to the stimulation to beoptimized so that the effects of the stimulation and the administrationof the pain treating agent can be cumulative (or preferably more thancumulative). Of course, the onset of administration of the pain treatingagent and the onset of low frequency stimulation may occur atsubstantially the same time. FIG. 18C-D, show that a pain treating agent(e.g., a δ-opioid agonist or an α2-adrenergic agonist) may beadministered (5160) in conjunction with high frequency stimulation(5150) in a manner similar to that described above with regard to aμ-opioid agonist and low frequency stimulation (FIGS. 18A-B). While notshown in FIG. 18, it will be understood that a pain treating agent maybe administered in conjunction with spinal cord stimulation.

Referring to FIG. 19, an example of how a first pain treating agent maybe administered in conjunction with low frequency stimulation and how asecond pain treating agent may be administered in conjunction with highfrequency stimulation is shown. As shown in FIG. 19, a μ-opioid agonistmay be administered (5180) in conjunction with low frequency stimulationapplied subcutaneously to a region in proximity to a source of pain(5170) and a δ-opioid agonist or an α₂-adrenergic agonist may beadministered (5200) in conjunction with high frequency stimulationapplied subcutaneously to a region in proximity to a source of pain(5190). As shown in FIG. 19, the administration of pain treating agentsand stimulation signals may occur in a cyclic fashion as follows: (i)administration of low frequency stimulation (5170), (ii) administrationof p-opioid agonist (5180), (iii) administration of high frequencystimulation (5190), (iv) administration of δ-opioid agonist or anα₂-adrenergic agonist (5200), (v) repeat at (i). Another example of howadministration of pain treating agents and stimulation signals may occurin a cyclic fashion is: (i) administration of p-opioid agonist (5180),(ii) administration of low frequency stimulation, (iii) administrationof δ-opioid agonist or an α₂-adrenergic agonist (5200), (iv)administration of high frequency stimulation (5190), (v) repeat at (i).Of course the order of administration of each individual component maybe modified and the onset of the administration of the pain treatingagent and the onset of the high or low frequency stimulation may occurat substantially the same time. The administration in such a cyclicmanner may reduce the tolerance that may develop to any given therapy(i.e., δ-opioid agonist, low frequency stimulation, p-opioid agonist orα₂-adrenergic agonist, and high frequency stimulation). While not shownin FIG. 19, it will be understood that a pain treating agent may beadministered in conjunction with spinal cord stimulation.

While the discussion with regard to FIGS. 17-19 refers to delivery of apain treating agent based on the status of stimulation therapy, it willbe understood that stimulation therapy may be applied based on thestatus of pain treating agent delivery.

Further it will be understood that it may not always be desirable toadminister (i) a δ-opioid agonist and high frequency stimulationconcurrently or (ii) μ-opioid agonist and low frequency stimulationconcurrently because cross-tolerance may develop. To reduce tolerance itmay be desirable to cycle between (i) high and low frequency stimulationand (ii) delivery of a δ-opioid agonist and a μ-opioid agonist, (a) highfrequency stimulation and delivery of a μ-opioid agonist and (b) lowfrequency stimulation and delivery of a δ-opioid agonist, etc. Thecycling period could be seconds, minutes, hours, days, weeks, or months.

Systems for Coordinated Delivery of Stimulation and Infusion Therapy

In various embodiments, the invention provides systems capable ofdelivering coordinated stimulation therapy and infusion therapy. Astimulation signal may be delivered at a predetermined time relative toinfusion of, e.g., a particular type of therapeutic agent, such as apain treating agent, or a therapeutic agent at a particular rate, etc.Of course, infusion of a therapeutic agent may be timed relative toapplication of a particular stimulation signal.

Referring to FIG. 20, the coordinated delivery of a stimulation therapyand an infusion therapy may involve communication between a stimulationmodule 5300 and an infusion module 5310. The stimulation module 5300 andthe infusion module 5310 may be housed in a single housing or may bepart of separate devices, such as an implantable pulse generator 14 oran implantable infusion device 5000. As shown in FIG. 20A, the infusionmodule 5310 may receive information regarding the status of thestimulation module 5300, such as whether the stimulation module 5300 isproducing a stimulation signal that may trigger a change in infusionparameters in the infusion module 5310. Similarly and as shown in FIG.20B, the stimulation module 5300 may receive information regarding thestatus of the infusion module 5310, such as whether the infusion module5310 is infusing an agent at a rate that may trigger a change ininfusion parameters in the stimulation module 5300. Of course theinformation may be bi-directional as shown in FIG. 20C; i.e., theinfusion module 5310 may receive information regarding the status of thestimulation module 5300 and the stimulation module 5300 may receiveinformation regarding the status of the infusion module 5310. Of course,there may be more than one infusion module 5310 and more than onestimulation module 5300 and communication may be coordinated between thevarious infusion modules 5310 and stimulation modules 5300 so thatstimulation at the particular parameters is applied to a particular bodylocation at an appropriate time relative to infusion with particularparameters at a particular body location. The communication between astimulation module 5300 and an infusion module 5310 may occur wirelesslyor through wires. If a stimulation module 5300 and an infusion module5310 are housed in separate devices, it may be desirable forcommunication to occur wirelessly, e.g. through telemetry. If astimulation module 5300 and an infusion module 5310 are housed in asingle device, it may be desirable for control of communication to occurthrough a processor (not shown) also housed within the device.

Referring to FIGS. 21A-B, stimulation module 5300 may include a pulsegeneration module 5320 and a stimulation control module 5330. Infusionmodule 5310 may include a pump module 5340 and a pump control module5350. Stimulation control module 5330 may receive information regardingthe status of infusion module 5310 and may control parameters of astimulation signal to be delivered. Similarly, pump control module 5350may receive information regarding the status of stimulation module 5300and may control parameters associated with infusion of a therapeuticagent.

Referring to FIG. 22, a control unit 5400 separate from stimulationmodule 5300 and infusion module 5310 may coordinate communicationbetween stimulation module 5300 and infusion module 5310. Whilecommunication is shown as bidirectional in FIG. 22, it will beunderstood that communication may be unidirectional between control unit5400 and stimulation module 5300 and infusion module 5310. For example,control unit 5400 may receive information regarding the status ofstimulation module 5300 and may transmit such information to pumpcontrol module 5350 of infusion module 5310. It will be understood thatinfusion module 5310 and stimulation module 5300 may communicatedirectly with each other.

Referring to FIGS. 23A-B, exemplary systems employing two infusionmodules 5310, 5310A and one stimulation module 5300 are shown. Suchsystems may be configured such that a first infusion module 5310delivers a first therapeutic agent and a second infusion module 5310Adelivers a second therapeutic agent. The timing of delivery of the firstand second therapeutic agents may be controlled relative to delivery ofa particular stimulation signal generated by stimulation module 5300 bycommunication between stimulation module and first and second infusionmodules 5310, 5310A. First infusion module 5310 and second infusionmodule 5310A may be configured to communicate with each other in variousembodiments. As shown in FIG. 23B, a separate control unit 5400 may beemployed to coordinate the timing of delivery of a first therapeuticagent from first infusion module 5310, a second therapeutic agent fromsecond infusion module 5310A, and a stimulation signal from stimulationmodule 5300.

Systems employing a stimulation module 5300 and two infusion modules5310, 5310A or an infusion module 5310 having multiple reservoirs 5020may be configured for treating pain. For example: first infusion module5310 may contain a reservoir 5020 housing a first pain treating agent;second infusion module 5310A may contain a reservoir housing a secondpain treating agent; and stimulation module 5300 may contain a pulsegeneration module 5320 capable of generating a high frequency electricalsignal and a low frequency electrical signal. The first pain treatingagent may be delivered to a location in the patient 15 at apredetermined time relative to the application of low or high frequencysignals, and the second pain treating agent may be delivered to alocation in the patient 15 at a predetermined time relative to theapplication of low or high frequency signals, as described hereinabove.

Control unit 5400 as discussed above with regard to FIGS. 22 and 23 maybe a programmer 4000, 5050 capable of providing instructions to bothstimulation module 5300 and infusion module 5310. The timing of deliveryof particular stimulation signals in a stimulation module 5300 andinfusion parameters in an infusion module 5310 may be coordinated bysuch a programmer 4000, 5050 at the time the programmer 4000, 5050instructs stimulation module 5300 and infusion module 5310 to deliverstimulation signals or therapeutic agent according to particularparameters over time. Referring to FIGS. 24A-B, programmer 4000, 5050may instruct stimulation module 5300 to generate first (e.g., lowfrequency) and second (e.g., high frequency) signals at a predeterminedtime or in a predetermined pattern (5500). Programmer 4000, 5050 maythen instruct, either concurrently or at a separate time, infusionmodule 5310 to deliver therapeutic (e.g., pain treating) agent at afirst rate at a predetermined time relative to the generation of thefirst and second signals (5510). Of course, programmer 4000, 5050 mayinstruct infusion module 5310 to deliver a therapeutic agent at a rateat a predetermined time (5520) and instruct stimulation module 5300 togenerate first and second electric signals at a predetermined timerelative to the delivery of the agent at the rate (5530), as show inFIG. 24B. To facilitate delivery of stimulation and infusion therapiesin a coordinated fashion, it may be desirable to synchronize stimulationmodule and infusion module. Such synchronization can occur through anyknown or future developed technique. Examples of suitable methods forsynchronizing two implanted devices are discussed in, e.g., publishedpatent application US20040133390A1: “Synchronization and calibration ofclocks for a medical device and calibrated clock.”

Programmer 4000, 5050 control unit 5400 may be a physician programmerunit or a patient programmer unit. For example, control unit 5400 may bea patient programmer 4000, 5050 capable of administering patientcontrolled analgesia (see, e.g. U.S. Patent Application No. 20030204274,published on Oct. 30, 2003). When a patient 15 has breakthrough pain,the patient may request delivery of enhanced pain therapy. When patient15 requests such therapy using a programmer 4000, 5050, programmer mayinstruct both the stimulation unit 5300 and infusion unit 5310 todeliver therapy at altered (relative to basal therapy) parameters. Forexample, if infusion module 5310 contains a μ-opioid agonist to bedelivered intrathecally, a patient request for additional therapy mayresult in the programmer instructing infusion module 5310 to deliver abolus of μ-opioid agonist, such as morphine, at a particular rate at andfor a particular time. Programmer 4000, 5050 may also substantiallysimultaneously or sequentially instruct stimulation module 5300 todeliver a low frequency stimulation signal for a period of time relativeto the administration of the bolus of μ-opioid agonist to enhance thepain treating effect of the bolus.

While not shown, it will be understood that one or more sensors may beemployed to effectuate coordinated delivery of pain treating agenttherapy and stimulation therapy. By way of example, control unit 1010 ofIPG 14 or control module 5330 of stimulation module 5300 may be operablycoupled to a sensor capable of detecting the presence or amount of apain treating agent and may adjust stimulation therapy output based onwhether a pain treating agent or an amount of a pain treating agent ispresent at a location in a patient 15. As another example, control unit5040 of infusion device 5000 or control module 5350 of infusion module5310 may be operably coupled to a sensor capable of detecting thepresence of a high frequency or low frequency signal (optionallyemploying appropriate bandwidth filters as necessary or desired) and mayadjust infusion therapy output based on whether a high or low frequencysignal is being applied at a location in a patient 15.

Coordination of System Components

Coordination of therapy delivery between stimulation module 5300 andinfusion module 5310 may occur in a variety of manners. FIGS. 25-30 showa few examples of how such coordination may occur.

FIG. 25 shows an example suitable for a system comprising a stimulationmodule 5300 and an infusion module 5310. As shown in FIG. 25, adetermination may be made as to whether a switch from generation of afirst electrical signal (e.g., low frequency) to a second electricalsignal (e.g., high frequency) has occurred (5600). If such a switch hasoccurred a change in infusion parameter for delivering a firsttherapeutic agent may be made at a predetermined time relative to theswitch (5610). If no such switch has occurred, the infusion parametersassociated with the first therapeutic agent may remain unchanged, whichmay mean that no agent is delivered (5620). Such a change in infusionrate relative to a switch in stimulation parameters may occur one time(e.g., as with a patient programmer request for additional pain therapy)or may occur in a continuous manner, as shown in FIG. 26, indefinitelyor for a defined period of time. It will be understood that the processoutlined above can readily be adapted to systems including two infusionmodules 5310, 5310A or an infusion module 5310 including two reservoirs5020, 5020A such that a first therapeutic agent is delivered if noswitch has occurred and a second therapeutic agent is delivered is aswitch has occurred.

FIG. 27 refers to a process that substantially incorporates the processshown in FIG. 26 and adds a determination as to whether a switch from asecond electrical signal (e.g., high frequency) to a first electricalsignal (e.g., low frequency) has occurred (5630). As with the processdiscussed with regard to FIG. 26, if a switch from a first to secondsignal has occurred (5600), a change in infusion parameter fordelivering a first therapeutic agent may be made at a predetermined timerelative to the switch (5610). As shown in FIG. 27, if a switch fromgeneration of a second electrical signal to generation of a firstelectrical signal has occurred (5630), a change in infusion deliveryrate (e.g., return to default or basal rate) of first therapeutic agentoccurs at a predetermined time relative to the switch (5620) until aswitch from first to second electrical signals occurs again (5600).

FIG. 28 shows a process suitable for a system including two infusionmodules 5310, 5310A or an infusion module 5310 having two reservoirs5020, 5020A, but otherwise is similar to the process shown in FIG. 27.As with the process discussed with regard to FIGS. 26-27, if a switchfrom a first to second signal has occurred (5600), a change in infusionparameter for delivering a first therapeutic agent may be made at apredetermined time relative to the switch (5610). As shown in FIG. 28,if a switch from generation of a second electrical signal to generationof a first electrical signal has occurred (5630), a second therapeuticagent can be delivered at a predetermined time relative to the switch(5640) until a switch from first to second electrical signals occursagain (5600), in which case the first therapeutic agent is againdelivered with the prior infusion parameters at a predetermined timerelative to the switch (5610). It will be understood that a switch fromfirst to second stimulation signals (5600) may stop or return to defaultor basal rate infusion of the second therapeutic agent and that a switchfrom second to first stimulation signals (5630) may stop or return todefault or basal rate infusion of the first therapeutic agent.

As shown in FIG. 29, the change in infusion parameters of the firsttherapeutic agent (5610) or the delivery of the second therapeutic agentat a predefined infusion rate (5640) or of the first agent at adifferent rate (5620) may be coordinated with whether a first electricalsignal is being generated (5650) or whether a second electrical signalis being generated (5660) rather than whether a switch from first tosecond signal (5600) or switch from second to first electrical signal(5630), as discussed with regard to FIGS. 25-28. For example, adetermination as to whether a first (5650) or second (5660) electricalsignal is being generated may occur at a time when a stimulation module5300 and an infusion module 5310 are being programmed or may occur at atime during operation of the stimulation module 5300.

As shown in FIG. 30, a stimulation module 5300 may respond or beprogrammed to generate a first (5670) or second (5680) electrical signalat a predetermined time relative to whether a first therapeutic agent isbeing delivered or being delivered at a particular rate (5690). It willbe understood that each of the processes discussed with regard to FIGS.25-29 may readily be modified according to the process described withregard to FIG. 30 such that stimulation module 5300 output is modifiedbased on status of pain treating agent delivery.

All patents, patent applications, technical papers, publications, anddevices cited herein are hereby incorporated by reference herein, eachin its respective entirety. As those of ordinary skill in the art willreadily appreciate upon reading the description herein, at least some ofthe devices and methods disclosed in the patents and publications citedherein may be modified advantageously in accordance with the teachingsof the present invention.

1. A system comprising: a pulse generator configured to alternatebetween generation of a first electrical signal and generation of asecond electrical signal; a first infusion device configured to delivera first therapeutic agent at a first rate at a first predetermined timethat is a first predetermined time interval before or after a time whenthe pulse generator switches from generation of the first signal togeneration of the second signal; and a control unit configured tocoordinate the delivery of the first therapeutic agent at the first ratefrom the first infusion device with the switch from the generation ofthe first signal to the generation of the second signal.
 2. The systemof claim 1, wherein the control unit provides information to theinfusion device regarding when the pulse generator switches fromgeneration of the first signal to generation of the second signal. 3.The infusion system of claim 1, wherein the control unit instructs thefirst infusion device when to deliver the first therapeutic agent. 4.The system of claim 1, wherein the control unit is an externalprogrammer unit.
 5. The system of claim 4, wherein the externalprogrammer unit provides instructions regarding therapy delivery to boththe pulse generator and the first infusion device.
 6. The system ofclaim 5, wherein the external programmer informs the first infusiondevice regarding when the pulse generator will switch from generation ofthe first signal to generation of the second signal at the time theprogrammer provides instructions regarding therapy to the first infusiondevice.
 7. The system of claim 1, wherein the control unit and the firstinfusion device are housed within a single housing.
 8. The system ofclaim 7, wherein the control unit is configured to communicatewirelessly with the pulse generator.
 9. The system of claim 1, whereinthe pulse generator and the control unit are configured to communicatewirelessly.
 10. The system of claim 9, wherein the first infusion deviceand the control unit are configured to communicate wirelessly.
 11. Thesystem of claim 1, wherein the first infusion device and the controlunit are configured to communicate wirelessly.
 12. The system of claim1, wherein the first infusion device delivers the first therapeuticagent at a second rate at a second predetermined time that is a secondpredetermined time interval before or after the time when the pulsegenerator switches from generation of the first signal to generation ofthe second signal, and wherein the control unit is further configured tocoordinate the delivery of the first therapeutic agent at the secondrate from the first infusion device with the switch from the generationof the first signal to the generation of the second signal.
 13. Thesystem of claim 1, wherein the first infusion device delivers the firsttherapeutic agent at a second rate at a second predetermined time thatis a second predetermined time interval before or after a time when thepulse generator switches from generation of the second signal togeneration of the first signal, and wherein the control unit is furtherconfigured to coordinate the delivery of the first therapeutic agent atthe second rate from the first infusion device with the switch from thegeneration of the second signal to the generation of the first signal.14. The system of claim 1, further comprising a second infusion devicethat delivers a second therapeutic agent at a second predetermined timethat is a second predetermined time interval before or after the timewhen the pulse generator switches from generation of the first signal togeneration of the second signal, wherein the control unit is furtherconfigured to coordinate the delivery of the second therapeutic agentfrom the second infusion device with the switch from the generation ofthe first signal to the generation of the second signal, and wherein thesecond predetermined time is the same or different than the firstpredetermined time.
 15. The system of claim 1, further comprising asecond infusion device that delivers a second therapeutic agent at asecond predetermined time that is a second predetermined time intervalbefore or after a time when the pulse generator switches from generationof the second signal to generation of the first signal, wherein thecontrol unit is further configured to coordinate the delivery of thesecond therapeutic agent from the second infusion device with the switchfrom the generation of the second signal to the generation of the firstsignal.
 16. The system of claim 1, further comprising a first reservoirand a second reservoir operably coupled to the first infusion device,the first reservoir being configured to house the first therapeuticagent.
 17. The system of claim 16, wherein the second reservoir isconfigured to house a second therapeutic agent.
 18. The system of claim17, wherein the first infusion device delivers the second therapeuticagent at a second predetermined time that is a second predetermined timeinterval before or after the time when the pulse generator switches fromgeneration of the first signal to generation of the second signal,wherein the control unit is further configured to coordinate thedelivery of the second therapeutic agent from the first infusion devicewith the switch from the generation of the first signal to thegeneration of the second signal, and wherein the first predeterminedtime and the second predetermined time is the same or different.
 19. Thesystem of claim 17, wherein the first infusion device delivers thesecond therapeutic agent at a second predetermined time that is a secondpredetermined time interval before or after a time when the pulsegenerator switches from generation of the second signal to generation ofthe first signal, wherein the control unit is further configured tocoordinate the delivery of the second therapeutic agent from the firstinfusion device with the switch from the generation of the second signalto the generation of the first signal.
 20. A system comprising: a pulsegenerator configured to alternate between generation of a firstelectrical signal and generation of a second electrical signal; and aninfusion device configured to deliver a first therapeutic agent at apredetermined time that is a predetermined time interval before or aftera time when the pulse generator switches from generation of the firstsignal to generation of the second signal.
 21. A method comprising:identifying whether a first predetermined electrical signal is beinggenerated by an implantable pulse generator via a control unit; andinstructing an infusion device to deliver a therapeutic agent at a rateif the predetermined electrical signal is being generated via thecontrol unit, wherein the control unit is separate from the implantablepulse generator and the infusion device.